Tetra Calcium Phosphate Based Organophosphorus Compositions and Methods

ABSTRACT

Compositions and methods of their use to adhere a variety of materials together are disclosed herein. The compositions include at least tetra calcium phosphate, an effective amount of a compound that is structurally similar to phosphoserine, and can be mixed with an aqueous solution. The compositions provide adhesive and cohesive strength in both wet and dry environments and exhibit significant bond strength upon curing.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit from the followingprovisional application Ser. No. 61/198,938, filed Nov., 12, 2008, Ser.No. 61/268,931, filed Jun. 18, 2009 and Ser. No. 61/237,762, filed Aug.28, 2009, the disclosures of which are hereby all incorporated byreference.

REFERENCE REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not applicable

SEQUENTIAL LISTING

Not applicable

BACKGROUND OF THE INVENTION

1. Field of the Invention

Tetra calcium phosphate based organophosphorus compositions that havesignificant cohesive and/or adhesive strength properties and also arephysiologically-well tolerated are disclosed herein.

2. Description of the Background of the Invention

Calcium phosphate composites are used as bone substitutes and bonegrafts. These calcium phosphate composites tend to form complexesprimarily between calcium-based salts through charge interactions. Thesecomposites are used as general bone void fillers and generally lack theadhesive strength sufficient to adhere or fix bones together, forexample, fractured surfaces. These prior compositions have insufficientchemical interaction between the calcium phosphate composite and thebone surface or other surface materials and lack sufficient strength tobe used to attach bone to bone or bone to other materials.

Certain marine species, such as tubeworms and sand castle worms, rely onsecreted proteins for adhesion mechanisms (“The tube cement ofPhragmatopoma californica: a solid foam,” Russell J. Stewart, James C.Weaver, Daniel E. Morse and J. Herbert Waite, Journal of ExperimentalBiology 207, 4727-4734, 2004). These adhesive proteins contain a highamount of phosphoserine relative to other amino acids. It should benoted that phosphoserine is also referred to as O-phosphoserine. This isan alternate name for the same material and in the present descriptionwe will use phosphoserine. The specific mechanism of the phosphoserineinvolvement with the proteins is not understood. However, phosphoserinehas been reported by Reinstorf et al. to be responsible for a specificinteraction with calcium containing hydroxyapatite (HA) of bone in U.S.Patent Application Publication No. 2005-0217538A1. In this publication,the authors describe calcium phosphate cements, which do not containtetra calcium based compositions, modified with phosphoserine in anamount from 0.5% to 5% weight of the composition. The phosphoserine isdescribed as aiding compressive strength and is used as a surface areamodifier in the bone cement material. When phosphoserine is used in therange from 0.5% to 5% weight of the composition, the resultingcompositions do not exhibit appreciable bone adhesion properties.

SUMMARY OF THE INVENTION

One embodiment of the present invention is a composition that comprisesa mixture of tetra calcium phosphate; and a compound of the formula

where A is O, CH₂, or S; R is H, NH₂, NHCO(CH₂)_(t)CH₃ where t is 0 to2, NH(CH₂)_(x)CH₃ where x is 0 to 3, NR1R2 where R1 is (CH₂)_(y)CH₃ andR2 is (CH₂)_(y)CH₃ where y is 0 to 2, (CH₂)_(z)CH₃ where z is 0 to 3,where m is 0 to 1, and where n is 0 to 3 and wherein the compound ispresent in an amount from about 10% by weight based on the combinedweight of the tetra calcium phosphate and the compound, and an aqueousmedium.

A further embodiment of the present invention comprises a method ofrepairing a hard surface comprising the steps of mixing a compositioncomprising an effective amount of tetra calcium phosphate and a compoundof the formula

where A is O, CH₂, or S; R is H, NH₂, NHCO(CH₂)_(t)CH₃ where t is 0 to2, NH(CH₂)_(x)CH₃ where x is 0 to 3, NR1R2 where R1 is (CH₂)_(y)CH₃ andR2 is (CH₂)_(y)CH₃ where y is 0 to 2, (CH₂)_(z)CH₃ where z is 0 to 3,where m is 0 to 1, and where n is 0 to 3 and wherein the compound ispresent in an amount from about 10% by weight based on the combinedweight of the tetra calcium phosphate and the compound, with sufficientaqueous medium to create a mixture; applying the mixture to the hardsurface to be repaired; and allowing the mixture to cure.

A still further embodiment of the present invention is a compositionthat comprises a mixture of tetra calcium phosphate; and a compound ofthe formula;

where A is O, CH₂, or S; R is H, NH₂, NHCO(CH₂)_(t)CH₃ where t is 0 to2, NH(CH₂)_(x)CH₃ where x is 0 to 3, NR1R2 where R1 is (CH₂)_(y)CH₃ andR2 is (CH₂)_(y)CH₃ where y is 0 to 2, (CH₂)_(z)CH₃ where z is 0 to 3,where m is 0 to 1, and where n is 0 to 3 and wherein the compound ispresent in an amount from about 10% by weight based on the combinedweight of the tetra calcium phosphate and the compound.

Yet another embodiment of the present invention is a kit for formingcalcium phosphate bone restorative product that comprises a compositioncomprising an effective amount of tetra calcium phosphate and a compoundof the formula

where A is O, CH₂, or S; R is H, NH₂, NHCO(CH₂)_(t)CH₃ where t is 0 to2, NH(CH₂)_(x)CH₃ where x is 0 to 3, NR1R2 where R1 is (CH₂)_(y)CH₃ andR2 is (CH₂)_(y)CH₃ where y is 0 to 2, (CH₂)_(z)CH₃ where z is 0 to 3,where m is 0 to 1, and where n is 0 to 3 and wherein the compound ispresent in an amount from about 10% by weight based on the combinedweight of the tetra calcium phosphate and the compound contained withina first container; and an aqueous medium contained within a secondcontainer.

An additional embodiment of the present invention comprises a method ofrepairing a bone structure that comprises the steps of applying acomposition comprising an effective amount of tetra calcium phosphateand a compound of the formula

where A is O, CH₂, or S; R is H, NH₂, NHCO(CH₂)_(t)CH₃ where t is 0 to2, NH(CH₂)_(x)CH₃ where x is 0 to 3, NR1R2 where R1 is (CH₂)_(y)CH₃ andR2 is (CH₂)_(y)CH₃ where y is 0 to 2, (CH₂)_(z)CH₃ where z is 0 to 3,where m is 0 to 1, and where n is 0 to 3 and wherein the compound ispresent in an amount from about 10% by weight based on the combinedweight of the tetra calcium phosphate and the compound directly to thebone structure to be repaired; and allowing the composition to harden bycombining in situ with aqueous based bodily fluids.

A still further embodiment of the present invention is a compositionthat comprises an effective amount of tetra calcium phosphate, acompound of the formula

where A is O, CH₂, or S; R is H, NH₂, NHCO(CH₂)_(t)CH₃ where t is 0 to2, NH(CH₂)_(x)CH₃ where x is 0 to 3, NR1R2 where R1 is (CH₂)_(y)CH₃ andR2 is (CH₂)_(y)CH₃ where y is 0 to 2, (CH₂)_(z)CH₃ where z is 0 to 3,where m is 0 to 1, and where n is 0 to 3 and an aqueous medium whereinthe composition has a tack state for up to about 12 minutes after thecomposition is mixed with the aqueous medium, has a separation strengthin the range of about 10 kPa to about 150 kPa during the tack state, hasa putty state for up to about 15 minutes after the composition is mixedwith the aqueous medium, and an adhesive strength upon curing of greaterthan 250 kPa.

An additional embodiment of the present invention comprises a method ofjoining bone to an other material comprising the steps of mixing acomposition comprising an effective amount of tetra calcium phosphateand a compound of the formula

where A is O, CH₂, or S; R is H, NH₂, NHCO(CH₂)_(t)CH₃ where t is 0 to2, NH(CH₂)_(x)CH₃ where x is 0 to 3, NR1R2 where R1 is (CH₂)_(y)CH₃ andR2 is (CH₂)_(y)CH₃ where y is 0 to 2, (CH₂)_(z)CH₃ where z is 0 to 3,where m is 0 to 1, and where n is 0 to 3 and wherein the compound ispresent in an amount from about 10% by weight based on the combinedweight of the tetra calcium phosphate and the compound, with sufficientaqueous medium to create a mixture and applying the mixture to a surfaceof the bone. The method further includes the steps of placing thesurface of the bone into contact with a material to be joined to thebone; and allowing the mixture to cure.

Other aspects and advantages of the present invention will becomeapparent upon consideration of the following detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 a graph of percentage porosity of selected compositions;

FIG. 2. is a graph comparing the screw pullout force for certaincompositions against a control that did not use any added composition asdescribed herein; and

FIG. 3 is a graph comparing the screw removal torque for certaincompositions against a control that did not use any added composition asdescribed herein.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The compositions as described herein have many unique properties notfound in prior calcium phosphate compositions. One particularlyimportant property is that the compositions have a tacky stateimmediately subsequent to mixing with an aqueous medium. This tackproperty is retained for a number of minutes, sometimes up to 12 minutesdepending on the application requirement, typically up to about 4minutes, and preferably up to about 2 minutes, after mixing with theaqueous medium. The time of the tacky state is dependent on a number offactors including relative ratio of the components, the particle sizesof the component materials, the presence of additives and the like.During this time the compositions will adhere bone to bone and bone toother materials, often without the need for external clamping or otherapplication of pressure. The tacky state is not so aggressive that thecomposition will permanently affix the materials together at this pointin time. Rather the tacky state can allow the materials to be movedrelative to each other and also to be re-opposed without appreciableloss of ultimate cured strength. This is important in a medical settingso that the user can make sure the bone and the other material to beadhered to the bone are in the proper position relative to each other.

The tacky state is followed by a putty state. In the putty state, thetacky property has substantially disappeared and the compositions can beshaped or sculpted. In addition, during the putty state, the compositioncan be formed into shapes or used to fill voids in bone in a mannersimilar to putty. This putty state is retained for a number of minutes,sometimes up to 15 minutes depending on the application requirement,typically up to about 8 minutes, and preferably up to about 5 minutes,after mixing with the aqueous medium. Like the tacky states, the puttystate is dependant on a number of factors including the relative ratioof the components, the presence of additives, the particle size of thecomponents and the like. Because the items to be affixed can berepositioned during the tacky state or the compositions can be shapedduring the putty state, this combined time of the tacky state and theputty state is some times referred to as the working time. Typicalcompositions have a working time of up to 8 minutes from initial mixingand often the working time is up to about 5 minutes after which time thecompositions have sufficiently begun hardening that further manipulationwill result in degradation of ultimate strength of the bond.

After the putty state, the compositions harden like a cement to form asubstantially permanent bond between the materials. In the cement state,the composition hardens and the materials that have been affixed to eachother cannot be separated without the application of significant force.The compositions typically will begin to harden within about 8 minutes,and often within about 5 minutes, after mixing with the aqueous medium.The amount of time to reach the cement state is also dependant of thesame factors listed above.

A further important property of the compositions is that thesecompositions have significant coherency and integrity within a wetenvironment. In the medical field, this would include a surgical site, awound or similar situation where blood and other bodily fluids arepresent. The tacky state, the putty state and the cement state all occurin either a wet environment or in a dry environment. In order to get thedesirable properties, the user need not ensure that the application siteis clean and dry. In a wet environment, the compositions tend to remaintogether and the presence of the liquid does not significantly affectthe integrity of the composition or the ultimate strength properties.

The compositions as described herein are useful in a wide variety ofmedical applications. One use of the compositions is to adhere bonefragments together within the body. This is useful, for example, duringsurgery to allow for temporary fixation prior to definitive hardwareplacement, and to enhance fracture fixation by adhering both load andnon-load bone fragments together alone or in the presence of appropriateimmobilization. The compositions also enhance screw or bone anchorfixation into low density cancellous bone at and/or after surgery, toallow screw fixation when the core diameter of the screw hole is largerthen the screw major diameter, for instance to reattach screws that havestripped from the surrounding material, to adhere a metal orbioresorbable plate to fractured bones allowing for reduction and/orelimination of metal or bioresorbable screws used to fix plate to bone.The compositions also have the capacity to enhance fixation of a jointreplacement prosthesis to bone (e.g. hip acetabular cup or femoralstem). The compositions adhere the junction of at least one of a tendon,ligament, cartilage, a bone graft, and/or dental implants to bone. Thecompositions may be used to support new bone growth for dental socket ordental ridge augmentation. The compositions have the capacity to adhereto bony defect perimeters while filling gaps creating a seal to preventleakage (e.g. cerebral spinal fluid). Furthermore, the compositions mayalso be used in ossicular chain reconstruction to adhere middle earossicles together. The adhesive properties of the compositions of thepresent invention to bone and bone to other materials make them usefulto provide bony contour for facial bone augmentation applications. Thesecompositions are also useful for gluing cancellous bones, cortical bonesand a combination of both, whether in fatty or greasy environmentspotentially without any surface pretreatment prior to application.

One particularly useful use of the compositions is as a bone restorativecomposition. By a bone restorative composition is meant a compositionthat is useful to restore and/or repair bone, such as bone adhesives,bone cements, bone glues, bone putties, bone void fillers, bonereplacement compositions, cements and/or adhesives to fix screws,implants and at least one of a tendon, ligament, cartilage, a bonegraft, and/or a dental implants to bone.

As noted above, the compositions have a tacky state shortly afterinitial mixing. This tacky state enables two items, such as two piecesof bone, bone and another material or two non-bone materials to be heldtogether by the composition itself, without the need for external force,until the composition sets to the final hardened cement state. Theamount of force needed to remove two opposed pieces of material fromeach other is the separation strength. For the composition as describedherein, these compositions have a separation strength during the tackystate within the first 4 minutes and preferably within the first 2minutes after initial mixing from about 10 kPa to about 250 kPa andpreferably from about 50 kPa to about 150 kPa. For certain applicationsit may be useful to have a longer tack state whereby certaincompositions have a separation strength which continues in this rangefor up to 12 minutes. This separation strength is sufficiently high thatthe items to be joined need not be held together unless there is anapposing strength of the items greater than the separation strength andalso, the items can still be repositioned or even reapposed without lossof ultimate bond strength.

It has been found that in the present compositions tetra calciumphosphate (TTCP) has unusual properties not shared by other calciumphosphate compositions. TTCP is the most basic of all the calciumphosphates; therefore, it readily reacts to acidic compounds. Whileother calcium phosphate compositions can be used in addition to theTTCP, the compositions must include an effective amount of TTCP. TheTTCP used in the present compositions can be made by a variety ofmethods. One such manufacturing method is disclosed by Chow and Takagiin U.S. Pat. No. 6,325,992, the disclosure of which is herebyincorporated by reference. The TTCP can be 100% pure material or caninclude other calcium and calcium phosphate materials as an impurity,e.g. α-TCP, CaO and/or HA.

A second necessary component of the compositions is a compound that hasthe following formula;

where A is O, CH₂, or S; R is H, NH₂, NHCO(CH₂)_(t)CH₃ where t is 0 to2, NH(CH₂)_(z)CH₃ where x is 0 to 3, NR1R2 where R1 is (CH₂)_(y)CH₃ andR2 is (CH₂)_(y)CH₃ where y is 0 to 2, (CH₂)_(z)CH₃ where z is 0 to 3,where m is 0 to 1, and where n is 0 to 3. Preferred compounds are thosewhere A is 0 or CH₂, R is H or NH₂, m is 0 or 1 and n is 0 or 1. Themost preferred compound is phosphoserine that has the followingstructure;

The compounds that are structurally similar to phosphoserine, whichcontain the reactive phosphonate or phosphate, and which have COOHfunctional groups, are capable of interacting with the Ca⁺ within theTTCP to form a calcium based matrix and are referred to as compoundsstructurally similar to phosphoserine in this description. Thecombination of these functional groups plus the geometry such as thechain length between the phosphorous and the COOH are unique aspects tothe molecules which affect the level of adhesive bonding strength tosubstrate surfaces such as bone and metal.

The preferred compound that is structurally similar to phosphoserine isphosphoserine which may be any form of phosphoserine, including thephospho-D-serine, phospho-L-serine or the phospho-DL-serine forms may beused. The stereochemistry of the phosphoserine does not seem to have anyimpact on the properties of the compositions disclosed herein.

It has been found that when the quantity of compounds that arestructurally similar to phosphoserine is increased beyond about 10% w/wof the combination of the compound and the TTCP, more generally in therange of about 10% to about 90%, more typically in the range of 15% toabout 50%, or preferably from about 20% to about 40%, the tack andadhesion properties of the resulting compositions were significant. Atsuch levels, the influence of compounds that are structurally similar tophosphoserine extends beyond internal interaction with the cement, butalso extends to significant binding with the hydroxyapatite architectureand proteins of bone. At below about 10% by weight of the compoundstructurally similar to phosphoserine, the compositions do not have atacky state and these compositions do not have adhesive properties.

Factors that may affect the length of the tacky state, the length of theputty states and the ultimate cure time, as well as strength propertiesof the compositions include: the percentage (w/w) TTCP and the compoundsthat are structurally similar to phosphoserine based solely on theweight of the TTCP and the compounds that are structurally similar tophosphoserine in the composition, the selection of the compounds thatare structurally similar to phosphoserine, the particle size of theTTCP, and the nature and quantity of any additives and/or fillers whichmay be combined to the composition to enhance the material properties.

The mean particle size of the TTCP should be below 1000 μm, preferably1-250 μm, most preferably 10-100 μm. As the mean particle size of theTTCP is reduced, the TTCP tends to dissolve too fast and thesecompositions may not be practical for all uses as disclosed herein. Onthe other hand if the TTCP has a mean particle size of greater thanabout 1000 μm, the intra-operative performance of the compositions maynot have the desired initial strength and be too slow to set. If alonger working time is desired, then TTCP with a larger mean particlesize can be used; however, if a shorter working time is desired, thenTTCP with a smaller mean particle sizes can be used. In certain useenvironments, compositions that have a multi-modal mean particle sizedistribution with, for example, one mode less then 50 μm and the othermode above 50 μm can provide unique properties such as a fast initialcure rate from the smaller mean particle size mode combined with higherintrinsic compression strength of the material from the larger meanparticle size mode.

The aqueous based mixing media useful for combining the TTCP andcompound that is structurally similar to phosphoserine powders caninclude water, buffers such as sodium phosphate, saline, and blood basedproducts such as whole blood, plasma, platelet rich plasma, serum,and/or bone marrow aspirate. The blood based products are used with thegoal of achieving enhanced rate of bone healing and remodeling. It isalso possible to use the compositions without premixing with an aqueousmedium if the composition is to be used in a sufficiently wetenvironment that the aqueous medium can be absorbed from the in situsite. In this situation, the composition can be dusted on or other wiseapplied to the desired site and then mixed with the liquids that arealready present at the site.

Additives may enhance the material properties. These properties includethe handling, porosity, intrinsic material strength, & bone healing rate(osteogenic). Suitable additives include: alpha or beta tri-calciumphosphate (α-TCP or β-TCP), calcium sulfate, calcium silicate, calciumcarbonate, sodium bicarbonate, sodium chloride, potassium chlorideglycerol phosphate disodium, amino acids such as serine, excess amountsof phosphoserine, polyols (such as glycerol, mannitol, sorbitol,trehalose, lactose, & sucrose), silk, keratin (primarily found in humanhair), autologous bone powder or chips, demineralized bone powder orchips, collagen, various biodegradable polymers such as poly ethyleneglycol (PEG), poly lactic acid (PLLA), poly glycolic acid (PGA), andcopolymers of lactic and glycolic acid (PLGA), further includingbiodegradable block polymers such as poly lactic acid(PLLA)-polyethylene glycol (PEG)-poly lactic acid (PLLA) block polymer,BMP7, stem cells, parathyroid hormone (PTH), bisphosphonates, andmixtures thereof. In addition, other additives and/or fillers could beincorporated which offer surgical visual aids & anti-infectiveproperties.

The α-TCP and β-TCP additive component typically is also in granularform. The granules presently contemplated have an overall diameter sizein the range of about 0.1 to 2 mm, or preferably between 0.5 to about 1mm. Larger and smaller granules can be used depending on the othercomponents of the composition and the desired end properties. In thepresent compositions, the particle size of the granules has an impact onthe mechanical strengths of the resultant compositions. The totalporosity of these granules is in the range of 40-80%, more preferably65-75%, and the average pore diameter size of the granules in thesecompositions is in the range of 20-500 μm, preferably 50-125 μm. Thegranules do not dissolve within the present embodiments during thecuring phase, but interacts as a solid particle with the othercomponents of the compositions. In the present compositions, theporosity and pore size listed here has an impact on the resorptioncharacteristics of the resultant compositions and to allow for bony ingrowth and healing as described by Dalal et al. in U.S. Pat. No.6,949,251.

The additives that affect the porosity include cement curing poreforming agents such as calcium carbonate or sodium bicarbonate, granuleswith pre-formed pores made from alpha or beta tri-calcium phosphate(α-TCP or β-TCP), biodegradable polymers usually in fiber form that openchannels or pores as they degrade relatively quick in vivo such as PGA,or copolymers such as PLGA, or biodegradable fibers that open channelsor pores as they degrade over relatively long time periods such as PLLA,silk, keratin, collagen, autologous bone powder or chips, ordemineralized bone powder or chips. Other biodegradable polymers not inthe form of fibers, rather powders, can be used such as PLLA, PGA, PLGA,PEG, or block polymers such as PLLA-PEG-PLLA. Small molecules may alsobe used which leach away relatively quickly from the cement as it cures;these materials may include sodium chloride, potassium chloride,glycerol phosphate disodium, polyols (such as glycerol, mannitol,sorbitol, trehalose, lactose, & sucrose), amino acids such as serine,and/or excess amounts of phosphoserine. Other materials that form poresmay dissolve or resorb over time in vivo and release from the cementopening pores; these materials include calcium sulfate, α-TCP or β-TCPpowder or granules. Granules can be used to alter the in vivo resorptionprofile, such as α-TCP or β-TCP granules, or hybrid granules made fromcalcium sulfate and α-TCP or β-TCP in which the calcium sulfate portionresorbs more quickly.

The additives that affect the bone healing rate driven by new boneingrowth can be influenced by the level of porosity of the cured cement.This rate can be manipulated by the number of pores and size of thepores created within the cured cement. Achieving such porosity up to 60%v/v was demonstrated by controlling the ratio of compositioningredients. The porosity that develops during the curing process can becontrolled by the amount of pore forming agent added (such as calciumcarbonate), the level of compound structurally similar to phosphoserineadded, the level of aqueous solution used, and/or the level of otheragents added to the composition. Increasing the porosity reduces thematerial intrinsic strength; however, a balance of porosity vs. strengthis critical for achieving the clinical application. Additives thatincrease the intrinsic material strength can be incorporated to offsetthe loss of strength by creating porosity.

The additives that increase the intrinsic material strength of the curedcement include silk, keratin, collagen, autologous bone powder or chips,demineralized bone powder or chips, calcium silicate, calcium sulfate,biodegradable polymers (such as PLLA, PGA, PLGA) or biodegradable blockpolymers (such as PLLA-PEG-PLLA), also granules made from calciumsulphate, α-TCP, β-TCP or hybrids thereof. These material additivesimprove the intrinsic strength or toughness by preventing crackpropagation in the cement when under load. These material additives canbe supplied as granules, powders or fibers. An important aspect of thesefibers is the size. The size can be defined by the aspect ratio(length:diameter). The preferred aspect ratio is from 2:1 to 50:1; morepreferable from 10:1 to 30:1. The overall length of the fiber can be upto 5 mm; however, since the material could be used as bone to boneadhesive, the length of the fiber may be more appropriate at lengths upto 2 mm. The additives can be added into the composition up to 30% w/wbased on the total weight of the composition to increase the intrinsicstrength of the material; however, as such levels the adhesiveproperties decrease; therefore, a balance between intrinsic strength andmaterial adhesive properties is required.

The additives that act as visual aids in the surgical procedure includecolorants such as a pigment or dye to aid in determining coverage anddepth of the applied cement or contrast agents such as barium salts indetermining depth on a radiograph.

Other additives can be incorporated into the compositions that enhancethe bone healing rate (osteogenic) These additives comprise a class ofosteogenic growth factors including bone morphogenetic proteins (BMP's),such as BMP 7, stem cells, parathyroid hormone (PTH) and/oranti-osteoporotic agents such as bisphosphonates can be contemplated forincorporation into the composition.

Other additives that can be incorporated into the composition areinfection preventatives such as broad spectrum antibiotics andanti-infectic additives.

While not wishing to be bound by theory, compositions of the presentdisclosure are believed to function as follows: the TTCP, which is basicin nature, reacts with the compound that is structurally similar tophosphoserine, which is acidic in nature, upon mixing with the aqueousmedium and forms a hardened, layered structure upon curing. Thisreaction is exothermic; the degree of exothermic activity depends on anumber of factors including the volume of the composition. The low pHnature of the compounds that are structurally similar to phosphoserineenable the hydroxyl of phosphate or phosphonate and COOH functionalgroup to bond through ionic interaction with the calcium ions fromwithin the TTCP. This resulting reactive intermediate continues acascade of ionic interactions with calcium and phosphate ions within theTTCP or HA on the bone surface or any other metal ions of the metalimplants. This series of interactions provides transient material havingthe tacky properties while curing and the adhesion strength thatincreases upon cure.

The exothermic properties of the composition when curing are prevalentwhen mixing as a large volume bone void filler (usually greater then 10cc) and this may serve as an effective means to kill the residual tumorcells locally that remain after surgical bone tumor removal.

The exothermic properties of the composition may lead to necrosis oflocal tissue and this also reduces the adhesive working time. The amountof heat released by the exothermic reaction is mainly influenced by thevolume of the composition, the size of the particles and the ratio ofcompound that is structurally similar to phosphoserine to TTCP. Withlarger volumes of composition, more heat is released to the surroundingtissue. With volumes less than or equal to 1 cc, the heat release isnegligible with maximum temperature reached during the curing of theadhesive being below 40° C. The higher volume compositions greater than1 cc, led to considerable heat release, even exceeding 60° C. incompositions greater than 5 cc. To manage this exothermic heat releaseto below 45° C., the particle size distribution of the TTCP, and theratio of TTCP to compound that is structurally similar to phosphoserinecan be chosen appropriately. The smaller TTCP particles dissolve andreact faster due to a higher specific surface area; therefore, to reducethe exothermic heat release, the composition can be adjusted by choosinga TTCP particle size distribution which generally has a mean particlesize greater than 15 μm, more specifically 25 μm. In addition, thegreater the amount of TTCP to the compound that is structurally similarto phosphoserine used, results in a faster reaction due to the number ofcalcium ions available for bonding. Exothermic heat release can belimited by adding more compound that is structurally similar tophosphoserine to the composition. To further reduce the exothermic heatrelease, endothermic additives can be incorporated into the compositionto slow the reaction rate; these include polyols (such as sorbitol ormannitol) or PEG. The factors discussed here can be chosen to designseveral compositions; all of which have exothermic profiles which limitor eliminate necrotic reactions to local tissues while tailoring thecompositions with sufficient working time for the clinical application.

The compositions when mixed with aqueous medium typically have a creamyor a tacky paste consistency initially. Also, the mixing of thecompositions with the aqueous medium does not require a high level offorce or shear and simple hand mixing, such as with a spatula, issufficient in most instances. It is envisioned that the presentcompositions may be applied via injection through a syringe or othersuitable pressurized implement, applied with a spatula, and as otherwisedesirable by a user. The creamy or tacky viscosity allows forapplication of the composition to the defect site for a defined periodof time. The compositions allow the bone to be repositioned severaltimes within 4 minutes and preferably within 2 minutes without losingtack properties. If the compositions need to be injected through asyringe or cannula, the viscosity of the composition during the workingtime can be important. For these situations, viscosities of thecompositions herein should be preferably below about 150 centipoise.

Still further embodiments have a consistency similar to putty. Theseembodiments are useful for filling larger defects, have sculptingproperties, or for mechanical interlocking into cancellous bone. Thesecompositions hold their cohesive, tacky, and sculpting properties over alonger period of time even when subjected to a wet field. Thecompositions have working time for sculpting sometimes up to 15 minutesdepending on the application requirement, typically up to about 8minutes, and preferably up to about 5 minutes, after mixing with theaqueous medium. Formulations with an increased amount of compound thatis structurally similar to phosphoserine greater than 25% w/w orincreased TTCP mean particle size greater than about 250 microns tend tohave longer working times and seem to be suitable for use in situationswere the putty will fill defects in structures that are well supportedby surrounding bone. In these situations the putty does not need toharden as fast provided it maintains its cohesive properties in the wetfield. Another property of the compositions is that the compositionswill adhere to themselves as well as to an external surface such asbone. This is useful in situations where a shape is formed during theputty state and this shape can then adhere to bone. Also, in someinstances a user may apply a mass of the composition to a bone or othersurface and then shape the composition into the final desired shapeduring the working time of the composition.

Compositions which have a putty consistency to be used a void filler canbe enhanced by incorporating macro porous granules or chips to allow fornew bone ingrowth. These granules may come from synthetic sources suchα-TCP or β-TCP granules or it may be preferred to select the granules orchips from autologous bone sources or demineralized bone to enhance thebone healing rate.

It is further envisioned that the cement compositions disclosed hereinmay be packaged into kits that may include a vial containing the TTCPwith the compound that is structurally similar to phosphoserinepre-filled together and packaged under vacuum, nitrogen, or dry air topreserve the shelf life. Further, if additives are used, they may beincluded within this vial or in a separate vial. The aqueous medium isprovided in a separate vial. The kit may include mixing bowls, stirringsticks, spatulas, syringes, and/or any other desirable component forapplication.

Composition of the current disclosure are envisioned to provide ease ofuse in different medical applications based on ease of application,duration of use before cure, resistance to in vivo environments,extended maneuverability of bone fragments and/or implant devices priorto cure onset, good load bearing capabilities after cure, and goodultimate bond strength. For example, compositions may have an adequateworking period after mixing sometimes up to 15 minutes depending on theapplication requirement, typically up to about 8 minutes or less, andpreferably up to about 5 minutes or less. Further, the relative force ofpressure required to inject the composition from an appropriately sizedsyringe may remain constant or below a certain injection force thresholdfrom the point of mixing and loading the syringe to the end of theworking period. It is contemplated that bone fragments adhered togetheror implanted devices may exhibit moderate separation strengths withinthe working period. Such moderate separation strengths may be exhibitedregardless of the relative compressive force used during apposition. Itis further contemplated that cement compositions of the presentdisclosure may have sufficient material cohesion when applied in moist,wet, greasy and/or fatty saline environments, such as in vivo settings,thereby reducing the need for surface preparation and maintaining a dryenvironment. As well, good capacity for supporting passive movement andmaintaining load and non-load bearing bone fragment alignment aftersurgery during initial rehabilitation period and active range of motionrehabilitation period are envisioned for cement compositionscontemplated herein.

Typical compositions exhibit an adhesive strength upon curing, typicallyafter greater than 10 minutes from initial mixing, in the range of about250 to about 2000 kPa on cancellous bone and from about 250 to about10,000 kPa on cortical bone in at least one of compression, tension,shear, and/or bending. Compositions can be chosen to achieve thestrength in these ranges; the level of strength required is dependentupon the clinical application. Also it is important to note that thecuring can be either in a wet environment, such as in bodily fluids, orin a dry environment, and the ultimate strength of the bond after curedoes not seem to be significantly affected.

In the following examples all shear, tension and bending testing wasdone using an Instron Force test machine setup as follows. For sheartesting the sample was supported and fastened to the machine at one endof the sample and the other end was left free and unsupported. For sheartesting the samples have a bond surface that was 90° to the face of thebone samples unless there was an indication that the bond surface was atan angle of 45° from the face of the bone surface. The force test probewas placed in plane against the top of the bond line of the sample andforce was applied until failure. For tension testing each end of thesample was clamped to the testing machine and the force was applied at90° to the bond to pull the sample apart. When the bond fails the resultwas recorded. For the 3 point bending testing each end of the sample wassupported without clamping the sample to create a span distance of 35mm. Force was applied by the force probe to the top of the sample at thecenter point (same position as the bond line) between both ends untilthe bond fails. The TTCP that was used in all the following examples wasa commercially available material that included from about 17% to 32% ofrelated impurities. These materials all contained about 68% to 83% TTCP.

Example 1

Each composition in Table 1 was mixed for 20 seconds in a polycarbonatebowl using either a polycarbonate pestle or spatula. After mixing, thecomposition was applied to both surfaces of bovine cortical bone cubesthat had apposing faces using a spatula. The faces were created witheither a 45° angle for the 45° shear/tension test (10×14 mm face) or a90° angle for isolated shear, tension, or bending tests (9×9.5 mm face).Prior to testing, the bone cubes were incubated within a phosphatebuffered saline (PBS) solution bath at 30° C. and had pre-dampenedsurfaces during composition application. By 90 seconds from the start ofmixing, the apposing faces were adhered together and aligned withminimal hand compression force for 10 seconds and were immediatelytransferred and submerged within a PBS solution bath held at 30° C. forthe duration of the cure time. If cured for longer then 10 min, thecubes were incubated at 37° C. After the cure time indicated, the cubeswere loaded onto the sample fixtures and tested on an Instron force testmachine. In the table, n=# is the number of replicates.

TABLE 1 Composition 1A 1B 1C TTCP 400 mg 400 mg 400 mg Phosphoserine 185mg 150 mg 250 mg Water 130 μl 130 μl 135 μl Adhesive Strength (kPa),1520 (n = 1) 3300 (n = 4) 2290 (n = 3) Cure = 5 min (45° Shear/ (Shear)(Shear) Tension)

Example 2

The compositions of Table 2 were prepared and tested in the same manneras in Example 1. All testing was on cortical bovine bone unlessotherwise indicated as cancellous bovine bone. All testing was conductedat 5 minutes cure unless otherwise indicated. All testing was 90° sheartesting unless otherwise indicated.

TABLE 2 Composition 2A 2B 2C 2D 2E TTCP 400 mg 400 mg 400 mg 400 mg 400mg Phosphoserine 185 mg 250 mg 267 mg 185 mg 280 mg β-TCP granules 100mg 133 mg 133 mg 100 mg 400 mg Water 130 μl 175 μl 146 μl Blood, fetal130 μl bovine 20% PEG 220 μl solution, Mol. Wt. = 3350, Adhesive 26901300 1620 2560 No tack to Strength (kPa) (n = 6); (n = 1); (n = 1); (n =3) surgical 2340 2130 2360 gloves (n = 6) (n = 1) (n = 1) during(Tension); @ @ working 6260 10 min 10 min period (n = 6) (3Pt cure curebending); 1020 (n = 6) cancellous; 450 (n = 6) cancellous (Tension); 860(n = 6) cancellous (3Pt bending)

Example 3

The compositions of Table 3 were prepared and tested in the same manneras in Example 1. All testing was on cortical bovine bone. All testingwas conducted at 5 minutes cure. All testing was 45° Shear/Tension.

TABLE 3 Composition 3A 3B 3C 3D TTCP 400 mg 400 mg 400 mg 400 mgPhosphoserine 185 mg 185 mg 185 mg 185 mg Water 130 μl 130 μl 130 μl 130μl α-TCP granules 100 mg Calcium sulfate powder 100 mg  50 mg 100 mgβ-TCP granules 100 mg  50 mg Adhesive Strength (kPa) 2609 (n = 3) 2321(n = 1) 2671 2314 (n = 1) (n = 1)

Example 4

The compositions of Table 4 were prepared and tested in the same manneras in Example 1. All testing was on cortical bovine bone. All testingwas conducted at 5 minutes cure. All testing was 45° Shear/Tension.

TABLE 4 Composition 4A 4B 4C TTCP 400 mg 400 mg 400 mg Phosphoserine 185mg Carboxy ethyl 185 mg phosphonate Phoshonoacetic acid 185 mg β-TCPgranules 100 mg 100 mg 100 mg Water 130 μl 130 μl 150 μl AdhesiveStrength (kPa) 2500 (n = 1) 653 (n = 1) 549 (n = 1)

Example 5

The compositions of Table 5A were prepared and tested in the same manneras in Example 1. The results of all testing are shown in Table 5B. Alltesting was on cortical bovine bone unless otherwise indicated. Alltesting was conducted at 5 minutes cure unless otherwise indicated. Alltesting was 45° Shear/Tension unless otherwise indicated.

TABLE 5A Composition 5A 5B 5C 5D 5E 5F 5G 5H TTCP, mg 400 400 400 400400 400 400 400 Phosphoserine, mg 185 185 185 185 185 185 185 185 Water,μl 130 130 130 130 130 130 130 130 β-TCP granules, mg 100 100 100 100100 100 100 100 Calcium carbonate 100  50  35  27  21  20  14  7 powder,mg

TABLE 5B Example Adhesive Strength (kPa) 5A  825 (n = 2);  190 (n = 2),cancellous 5B 1496 (n = 2)  423 (n = 3), cancellous 5C No strength data5D  320 (n = 1) (Shear)  720 (n = 1) @ 10 min cure (Shear) 5E  300 (n= 1) (Shear)  750 (n = 1) @ 10 min cure (Shear) 5F 1830 (n = 6) (Shear)1390 (n = 6) (Tension) 3930 (n = 6) (3Pt Bending)  660 (n = 6),cancellous (Shear)  660 (n = 6), cancellous (3Pt bending) 5G  410 (n= 1) (Shear)  800 (n = 1) @ 10 min cure (Shear)  745 (n = 2) (3Ptbending) 5H 1500 (n = 1) @ 10 min cure (Shear)

Example 6

Compositions with enhanced bony in-growth properties are important forclinical use. This can be achieved by enhancing the porosity of thecompositions. Certain compositions listed in FIG. 1 were prepared andtested in the same manner as in Example 1 and formed into thin disks.Each disc was 10 mm in diameter and 2 mm in height. Each sample wasallowed to cure at 37° C. for 24 hrs submerged in PBS solution. Aftercuring, the sample was dried over night in a desiccator. The sampleporosity was analyzed by Mercury Intrusion Porosimetry. The results ofall testing is shown in FIG. 1. The Y axis is the percent porosity. Theresults indicate the porosity of the cement as a function of the levelof both the pore forming agent added and level of phosphoserine added.

Example 7

The compositions of Table 7 were prepared and tested in the same manneras in Example 1. All testing was on cortical bovine bone. All testingwas conducted at 5 minutes cure. All testing was 45° Shear/Tension.

TABLE 7 Composition 7A 7B 7C TTCP 400 mg 400 mg 400 mg Phosphoserine 185mg 185 mg 185 mg Water 130 μl 130 μl 130 μl β-TCP granules 100 mg 100 mg100 mg Sodium Chloride  10 mg  25 mg Glycerol phosphate  25 mg disodiumAdhesive Strength (kPa) 2036 (n = 1) 778 (n = 2) 1931 (n = 1)

Example 8

The compositions of Table 8 were prepared and tested in the same manneras in Example 1. All testing was on cortical bovine bone. All testingwas conducted at 5 minutes cure. All testing was 45° Shear/Tensionunless otherwise indicated.

TABLE 8 Composition 8A 8B 8C 8D TTCP 400 mg 400 mg 400 mg 400 mgPhosphoserine 250 mg 250 mg 185 mg 185 mg Water 130 μl 130 μl 130 μl 130μl Serine  33 mg  16 mg Mannitol  25 mg Trehalose  60 mg β-TCP granules100 mg 100 mg Adhesive 160 (n = 1) 750 (n = 1) 1603 (n = 1) 386 (n = 1)Strength (kPa) (Shear); (Shear); 610 (n = 1) 1610 (n = 1) @ 10 @ 10minute cure minute cure (Shear) (Shear)

Example 9

The compositions of Table 9 were prepared and tested in the same manneras in Example 1. All testing was on cortical bovine bone unlessotherwise indicated. All testing was conducted at 5 minutes cure unlessotherwise indicated. All testing was 45° Shear/Tension unless otherwiseindicated.

TABLE 9 Composition 9A 9B 9C TTCP 400 mg 400 mg 400 mg Phosphoserine 185mg 250 mg 250 mg Water 140 μl 175 μl 175 μl β-TCP granules 100 mg 133 mg133 mg Calcium carbonate  14 mg  14 mg powder Calcium silicate 100 mgSilk, braided & ground  7 mg Bovine cortical bone  53 mg powder AdhesiveStrength (kPa) 2610 (n = 1); 5645 (n = 2) @ 4360 (n = 2) @ 350 (n = 1)10 min cure (3 10 minute cure cancellous pt bending) (3 Pt bending)

Example 10

The compositions of Table 10 were prepared and tested in the same manneras in Example 1. All testing was on cortical bovine bone unlessotherwise indicated. All testing was conducted at 10 minutes cure unlessotherwise indicated. All testing was 3 Pt bending unless otherwiseindicated.

TABLE 10 Composition 10A 10B 10C TTCP 400 mg 400 mg 400 mg Phosphoserine250 mg 250 mg 250 mg Water 175 μl 175 μl 135 μl Calcium Carbonate  14 mg 14 mg  14 mg β-TCP granules 133 mg 133 mg 133 mg Collagen (Type 1)  53mg PLGA (10:90) fiber  25 mg PLGA (50:50) fiber  7 mg Adhesive Strength(kPa) 1925 (n = 2) 4680 (n = 3) 4730 (n = 2)

Example 11

The compositions of Table 11 were prepared and tested in the same manneras in Example 1. All testing was on cortical bovine bone unlessotherwise indicated. All testing was conducted at 10 minutes cure unlessotherwise indicated. All testing was 3 Pt bending unless otherwiseindicated.

TABLE 11 Composition 11A 11B 11C TTCP 400 mg 400 mg 400 mg Phosphoserine267 mg 185 mg 250 mg Water 160 μl 130 μl 175 μl β-TCP granules 100 mg100 mg 133 mg Calcium carbonate powder  14 mg PLGA (50:50) powder  7 mgPLLA-PEG-PLLA  10 mg (5k:1k:5k) block copolymer Keratin fiber (Human  7mg hair) Adhesive Strength (kPa) 2825 (n = 2) 1819 (n = 1) @ 4950 (n =2) 5 min cure (45° Shear/Tension)

Example 12

The compositions of Table 12 were prepared and tested in the same manneras in Example 1. All testing was on cortical bovine bone unlessotherwise indicated. All testing was conducted at 10 minutes cure unlessotherwise indicated. All testing was 3 Pt bending unless otherwiseindicated.

TABLE 12 Composition 12A 12B 12C TTCP 400 mg 400 mg 400 mg Phosphoserine250 mg 185 mg 250 mg Water 175 μl 160 μl 130 μl β-TCP granules 133 mg100 mg 133 mg Calcium carbonate powder  14 mg  14 mg Osigraft(Collagen +  53 mg BMP7) BMP7 250 μg 200 μg Lactose  7 mg  5.6 mgAdhesive Strength (kPa) 2275 (n = 2) 2530 (n = 2) 6635 (n = 2)

Example 13

Formulations 2A and 5F were prepared and tested in the same manner as inExample 1 on both cortical and cancellous bone. Formulations 2A and 5Fare similar except that composition 5F includes calcium carbonate. Thecure time is shown in Tables 13A and 13B.

TABLE 13A Cortical Bone Cure Time Composition 2A (n = 6) Composition 5F(n = 6) Tension 2 min 1.10 +/− 0.14 0.58 +/− 0.42 5 min 2.34 +/− 0.351.39 +/− 0.35 Shear 2 min 1.63 +/− 0.30 1.33 +/− 0.20 5 min 2.69 +/−0.30 1.83 +/− 0.33 3 Pt 2 min 3.91 +/− 0.33 2.25 +/− 0.70 Bending 5 min6.26 +/− 0.31 3.93 +/− 0.80 24 hr 7.79 +/− 1.20 4.47 +/− 0.39 1 wk 7.16+/− 0.36 5.98 +/− 1.08

TABLE 13B Cancellous Bone Cure Time Composition 2A (n = 6) Composition5F (n = 6) Tension 2 min 0.25 +/− 0.05 0.24 +/− 0.05 (n = 4) 5 min 0.45+/− 0.11 0.41 +/− 0.08 (n = 4) Shear 2 min 0.58 +/− 0.17 0.36 +/− 0.10 5min 1.02 +/− 0.19 0.66 +/− 0.12 3 Pt 2 min 0.72 +/− 0.06 0.32 +/− 0.23Bending 5 min 0.86 +/− 0.11 0.66 +/− 0.28 24 hr 1.36 +/− 0.09 1.31+/−0.27 1 wk ND ND ND = No Data

Example 14

In order to see if the compositions can be used to fill a gap in bone,Formulations 1B and 1C were prepared and tested in the same manner as inExample 1. The bone cubes used for testing in Table 14 had apposingfaces measuring 9×9.5 mm. The faces were cut at 90° angle. Prior totesting, the bone cubes were incubated within a phosphate bufferedsaline (PBS) solution bath at 30° C. To simulate a gap, 2 mm ofcomposition was placed between one pair of bone while the no gap had asmall amount, less than 0.25 mm thickness applied. The cure time isshown in Table 14. After the cure time indicated, the cubes were loadedonto the sample fixtures and tested on an Instron force test machine inthe shear plane. A commercial product Mimix QS was prepared according todirections and tested as a control:

TABLE 14 Shear Strength (MPa) 5 min Cure 10 min Cure Bovine CorticalBones Adhesive Strength No Gap (<0.25 mm) Between Bones Composition 1B(n = 6) 3.30 +/− 0.15 3.20 +/− 0.57 Composition 1C (n = 6) 2.29 +/− 0.10 3.00 +/− 10.28 Mimix QS (n = 6) Control 0.09 +/− 0.8  0.99 +/− 0.20Bovine Cortical Bones Adhesive Strength 2 mm Gap Between BonesComposition 1C applied at 2.29 +/− 0.10  3.00 +/− 10.28 1.5 min (n = 6)Composition 1C applied at 1.21 +/− 0.23 1.91 +/− 0.60 2.5 min (n = 5)Composition 1C applied at 0.46 +/− 0.03 0.99 +/− 0.28 3.5 min (n = 3)

Example 15

In order to see the effect of fibrous materials added as an intrinsicstrength additive, a series of compositions set out in Table 15 wereprepared and tested in the same manner as in Example 1. The bone cubesused for testing in Table 15 had apposing faces measuring 9×9.5 mm. Thefaces were cut at 90° angle. The cure time was 10 minutes. After thesamples cured, the cubes were loaded onto the 3 pt bending samplefixture and tested on an Instron force test machine.

TABLE 15 3 Pt Bending Strength (MPa) @ 10 Min Composition CureComposition 5G, No fiber (n = 2) 0.75 Composition 9B, silk fiber (n = 2)5.65 Composition 10B, PLGA fiber (n = 2) 4.68 Composition 9C, corticalbone powder (n = 2) 4.36 Composition 11C, keratin hair fiber (n = 2)4.95The addition of fibers as an additive has a positive effect on thebending strength of the samples tested compared to a sample with nofiber as an additive.

Example 16

In order to test the effectiveness of the present compositions inbinding bone to metals used in surgery such as screw augmentation, asample of cancellous bone cube was drilled down the center with a drillhaving a diameter of 2.7 mm to a depth of 10 mm. The cancellous bonecube samples used for screw augmentation testing were from bovine sourceand had a density of 0.26+/−0.13 g/cm̂2 based on PIXA densitometry scans.Each bone cube sample measured 10 mm×10 mm in cross section×2.5 cm inlength. A stainless steel, cancellous bone screw with an outside threaddiameter of 4 mm with 7 mm of thread length was engaged into the drilledhole. The threads were fully engaged into the bone; however, the shankor shaft of the screw between the threads and screw head was leftexposed above the surface of the bone leaving a gripping space of 5 mm.The sample was clamped into a fixed vice located within an Instron loadmachine. A test fixture gripped under the head of the screw and themaximum force required to pull the screw from the bone at a rate=2mm/min was measured. After the screw was pulled out, the stripped holeand surrounding cancellous bone pores were filled with 0.2-0.3 cc withComposition 1C using a 3 cc Terumo syringe and the screw was re-insertedinto the stripped hole which was filled with the composition while itwas in the working period. The composition was allowed to cure at 37° C.in a humidity chamber for 10 minutes. The screw pullout force was thanre-tested demonstrating the screw augmentation properties of thecomposition. The results of the tests are shown in FIG. 2. The Y axis onthe drawing is pullout force in Newton (N). The control screw pulloutforce was 143+/−76 N (n=11); and the screw pullout force augmented withComposition 1C was 360.0+/−82 N (n=11). This was on average a 213%increase in pullout strength compared to the control.

Example 17

Example 16 was repeated except that the Instron testing was set up totest removal torque. Each bone cube sample was clamped into a fixedvice. A hand held torque gauge with appropriate tip was inserted intothe head of the screw and the maximum torque required to remove thescrew from the bone was measured. From the opposite end of the same cube(to mimic the same bone density), the sample was drilled down the centerof the cube with a drill with a diameter of 2.7 mm and to a depth of 10mm; however, this hole and the surrounding cancellous bone pores werefilled with 0.2-0.3 cc of Composition 1C using a 3 cc Terumo syringe andthe screw was inserted into the drilled hole which was filled with thecomposition while it was in the working period. The composition wasallowed to cure at 37° C. in a humidity chamber for 10 minutes. Thescrew removal torque was measured demonstrating the screw augmentationproperties of the composition. The results of the tests are shown inFIG. 3. The Y axis on the drawing is removal torque in Newton-centimeter(N-cm). The control screw removal torque was 4.7+/−0.8 N-cm (n=8); andthe Composition 1C screw removal torque was 26.9+/−8.7 N-cm (n=8). Thiswas on average a 480% increase in removal torque compared to thecontrol.

Example 18

The injectability into small bone void or onto bone surfaces using handforce was tested as follows. Composition 1C was mixed for 20-30 secs at18-22° C. in an ambient environment using a spatula or pestle. Aftermixing, the composition was loaded into a 3 cc Terumo syringe and thecomposition was injected through the luer lock nozzle tip with a peakforce not exceeding 150 N during the working period up through 3 min 30sec from the start of mixing.

Example 19

Composition tack and bone re-apposition properties were evaluatedthroughout the working period. Prior to composition application, thebone cubes were incubated in a PBS solution bath held at 30° C. The bonecubes were removed from the bath for testing and the surfaces remainedwet. The bone cubes were mounted into clamps (top and bottom) invertical axis alignment within the Instron machine. A small gap ofapproximately 1 cm was between the top surface of the bottom cube andthe bottom surface of the top cube. The Instron machine was located atroom temperature conditions of 18-22° C. Immediately after mounting thebone cubes, Composition 1C was mixed per the instructions in Example 18.After mixing, the composition was applied to the top surface of thebottom bone cube using a spatula. After application, the Instron testprogram was run at 1 min from the start of mixing. The Instron programprofile started by moving the top clamp down such that the bottomsurface of the top bone cube came into contact with the upper surface ofthe bottom bone cube with a compression force of 5 N held for 10 seconds(apposition). The Instron then moved the top clamp in the verticaldirection at 2 min/min to separate the bone cubes, thus measuring theseparation strength of the composition (tack property). This test wasrepeated at consecutive time periods throughout the tack state (at 2 minand at 3.5 min from the start of mixing), demonstrating there-apposition tack property of the composition. The bone fragmentsexhibited tack or separation strength, usually in the range of about50-150 kPa of tension strength at these time points. Immediately afterthe bones were separated at 3.5 min, the bones were re-apposed and thecomposition was allowed to cure at room temperature for up to 6.5 minfrom the start of mixing and the final separation strength was measuredwhich was typically greater then 1 MPa. This demonstrated that thecomposition allows the bone cubes to be reapposed several timesthroughout the tack state, without compromising the final separationstrength upon cure. This tack and re-apposition property is present notonly in tension, but also in the shear and bending planes.

Example 20

Sufficient material cohesion in a wet surgical field was evaluated.Composition 1C was mixed per the instructions in Example 1. By 2 minfrom the start of mixing, the composition as a solid mass was submergedinto water, PBS (pH was neutral 7.2-7.4), or blood at 37° C. After 24hrs of incubation, the fluid containing any eluded particulate orsoluble molecules from the composition was collected and visuallynegligible. In comparison to other commercially available calciumphosphate cements, such as HydroSet® Injectable HA Bone Substitute, thevisual amount of particulate or soluble molecules in the compositionelution was significantly less, demonstrating improved compositioncohesiveness when subjected to a wet field environment.

Example 21

Maintenance of bone fragment alignment to allow definitive hardwareplacement is critical in surgery. Composition 2A was mixed, applied tobones, and submerged to cure in a PBS bath at 30° C. as per theinstructions in Example 1. By 2-10 minutes of cure time the adhesiveseparation strength increased to the range of 1-4.5 MPa in shear andtension strength, and in the range of 3-10 MPa in 3 pt bending strength.This strength would hold the fragments together intra-operatively toallow drilling of bone and placement of appropriate immobilization(definitive hardware fixation) such as plates and screws (metal orresorbable). This capacity eliminates or reduces the need to use K-wiresor other temporary metal fixation devices, which can be difficult andawkward to use, as a temporary means to augment the bone fixationintra-operatively to allow appropriate immobilization.

Example 22

Capacity to bind and prevent calcium based granule migration from theputty material was evaluated. Composition 2B, which contains β-TCPgranules, was mixed per the instructions in Example 1 and could bemolded during the working period into any desired shape for the intendeddefect. Further in vitro testing demonstrated these compositions whilein the working period maintained consistency and prevented granulemigration from the putty matrix when submerged in PBS held at 37° C. andmaintained over a time period of at least 2 weeks. The β-TCP granulesdid not migrate from the putty; rather they were entrapped within theputty matrix.

Example 23

Composition 2B exhibits tack properties immediately after mixing whichsticks to surgical gloves. When the intended use of the composition is abone void filler to be applied manually by the surgeon's hands, thistack property may be undesirable for surgeons. This tack property to thegloves can be masked while maintaining the cohesive properties of thecomposition by adding PEG to the composition. Composition 2E containingPEG demonstrated this effect.

Example 24

Compositions that exhibit exothermic properties while curing can bemitigated by adjusting variables as displayed by the compositions inTable 16. These compositions were mixed as described in Example 1 andthen a thermocouple was placed into the middle of the composition whileit was curing in each bowl. The temperature measurements were recordedover time. Compositions mixed as smaller volumes and using largerparticle size TTCP had lower exothermic properties as did compositionsthat incorporated additives like sorbitol.

TABLE 16 Composition 1C was tested at various volumes of material (SmallTTCP mean particle size used) Component 1 cc 3 cc 5 cc TTCP (Particlesize 1600 mg 4800 mg 8000 mg Mean = 15-20 μm) Phosphoserine 1000 mg 3000mg 5000 mg Water 532 μl 1595 μl 2660 μl Max Temperature  38.2° C.  59.5°C.  69.0° C. during cure Composition 1C was tested at various volumes ofmaterial (Large TTCP mean particle size used) Component 3 cc TTCP(Particle size 4800 mg Mean = 25-35 μm) Phosphoserine 3000 mg Water 1595μl Max Temperature  44.8° C. during cure Composition 2A was tested atvarious volumes of material (Small TTCP mean particle size used)Component 1 cc 3 cc 5 cc TTCP (Particle size 1600 mg 4800 mg 8000 mgMean = 15-20 μm) Phosphoserine 740 mg 2200 mg 3700 mg β-TCP granules 400mg 1200 mg 2000 mg Water 520 μl 1595 μl 2660 μl Max Temperature  43.1°C.  65.5° C.  73.6° C. during cure Composition 2A (with Sorbitol added)was tested at various volumes of material (Small TTCP mean particle sizeused) Component 5 cc TTCP (Particle size 8000 mg Mean = 15-20 μm)Phosphoserine 3700 mg β-TCP granules 2000 mg Sorbitol  250 mg Water 2600μl Max Temperature  50.8° C. during cure

Comparative Example 1

TTCP is a unique component of all the calcium based materials whichinteracts with the compounds that are structurally similar tophosphoserine to exhibit the range of useful properties described inthis invention. Table 17 demonstrates this effect using the followingcalcium based powders in place of TTCP (Composition 1C): dicalciumphosphate dihydrate (DCPD), monocalcium phosphate monohydrate (MCPM),HA, β-TCP, octacalcium phosphate (OCP), & α-TCP. These compositions weremixed and applied to cortical bone cubes as described in Example 1. At1.5 min from the start of mixing, the bone cubes were submerged in a PBSbath held at 30° C. In addition, a small amount of the composition (0.25cc) was rolled into a ball and dropped into a vial containing 5 cc ofPBS solution at 30° C. to observe the particulate washout during thecure. After mixing, compositions 17A through 17E all resulted in creamycompositions, but none had tack properties which were highly evidentwith composition 1C (TTCP based). Further, these compositions hadsignificant visual particulate washout and failed to adhere the bonecubes as they fell apart either immediately during placement or within 3minutes of being submerged in the PBS bath. Composition 17F has someappreciable tack properties; however, there was visual particulatewashout observed in the PBS solution and moreover the adhesive strengthwas inferior in comparison to 1C.

Composition 1C 17A 17B 17C 17D 17E 17F TTCP 400 mg DCPD 400 mg MCPM 400mg β-TCP 400 mg HA 400 mg OCP 400 mg α-TCP 400 mg Phosphoserine 250 mg250 mg 250 mg 250 mg 250 mg 250 mg 250 mg Water 130 μl 130 μl 130 μl 130μl 130 μl 130 μl 130 μl Tack properties ^(A) ^(C) ^(C) ^(C) ^(C) ^(C)^(B) Wet field cohesion in putty state ^(D) ^(F) ^(F) ^(F) ^(F) ^(F)^(E) Adhesive strength, kPa 2290 0 0 0 0 0 250 (n = 3) (n = 3) (Shear)(Shear) ^(A)Composition has sticky properties to bone, metal surfaces,and surgical gloves ^(B)Composition has some sticky properties to bone,metal surfaces, and surgical gloves ^(C)Composition has creamyproperties, but does not stick to bone, metal, or surgical gloves^(D)Putty remained intact as a solid mass, no visual particulate washout^(E)Putty disintegrated partially, moderate visual particulate washout^(F)Putty disintegrated completely, significant visual particulatewashout

These compositions as disclosed in this specification can be used for avariety of medical applications. These include the capacity to allow orenhance fracture fixation by adhering both load and non-load bonefragments together alone or in the presence of appropriateimmobilization (definitive hardware fixation); capacity to adhere middleear ossicles and prosthesis together for ossicular chain reconstruction;capacity to enhance screw or bone anchor fixation in low densitycancellous bone at and/or after surgery; capacity to allow screwfixation when the core diameter of the screw hole in bone is larger thenthe screw major diameter; capacity to provide bony contour and/or facialbone augmentation properties; capacity to adhere a metal orbioresorbable plate to fractured bones allowing for reduction and/orelimination of metal or bioresorbable screws used to fix plate to bone;capacity to enhance fixation of a joint replacement prosthesis to bone(e.g. hip acetabular cup or femoral stem), capacity to adhere thejunction of at least one of a tendon, ligament, cartilage, a bone graft,and/or a dental implants to bone; capacity to adhere to bony defectperimeters while filling gaps creating a seal to prevent leakage (e.g.cerebral spinal fluid), and capacity to support new bone growth fordental socket or dental ridge augmentation. The compositions may beuseful in human use applications and are also useful in veterinaryapplications. Lastly, the compositions may be useful in similarnon-medical applications (e.g. carpentry, construction, under water use)as the compositions will adhere to a wide variety of surfaces includingwood, glass, certain plastics, plaster, metals of all types, ceramicmaterials and the like.

INDUSTRIAL APPLICABILITY

Numerous modifications to the present invention will be apparent tothose skilled in the art in view of the foregoing description.Accordingly, this description is to be construed as illustrative onlyand is presented for the purpose of enabling those skilled in the art tomake and use the invention and to teach the best mode of carrying outsame. The exclusive rights to all modifications which come within thescope of the appended claims are reserved.

1-19. (canceled)
 20. A method of repairing a hard surface comprising thesteps of: mixing a composition comprising an effective amount of tetracalcium phosphate and a compound of the formula

where A is O, CH2, or S; R is H, NH2, NHCO(CH2)tCH3 where t is 0 to 2,NH(CH2)xCH3 where x is 0 to 3, NR1R2 where R1 is (CH2)yCH3 and R2 is(CH2)yCH3 where y is 0 to 2, (CH2)zCH3 where z is 0 to 3, where m is 0to 1, and where n is 0 to 3 and wherein the compound is present in anamount from about 10% to about 90% by weight based on the combinedweight of the tetra calcium phosphate and the compound, with sufficientaqueous medium to create a mixture; applying the mixture to the hardsurface to be repaired; and allowing the mixture to cure.
 21. The methodof claim 20 wherein the hard surface is bone.
 22. The method of claim 21wherein the mixture is applied to a void in the bone to fill the void.23. The method of claim 20 wherein the compound is present in an amountfrom about 15% to about 50% by weight based on the combined weight ofthe of the tetra calcium phosphate and the compound.
 24. The method ofclaim 20 wherein the compound is present in an amount of about 20% toabout 40% by weight based on the combined weight of the of the tetracalcium phosphate and the compound.
 25. The method of claim 20 whereinthe compound is selected from the group consisting of phosphoserine,carboxy ethyl phosphonate, phoshonoacetic acid, and mixtures thereof.26. The method of claim 20 wherein R is H, or NH2.
 27. The method ofclaim 20 wherein the compound is phosphoserine.
 28. The method of claim20 wherein the composition has a mean particle size of less than 1000microns.
 29. The method of claim 20 wherein the aqueous medium is ablood based product.
 30. The method of claim 20 wherein the aqueousmedium is water.
 31. The method of claim 20 wherein the compositionfurther includes an additive.
 32. The method of claim 20 wherein themixture has a tack state for up to about 12 minutes, preferably for upto about 4 minutes, and most preferably for up to about 2 minutes, aftermixing with the aqueous medium.
 33. The method of claim 32 wherein themixture during the tack state has a separation strength in the range ofabout 10 kPa to about 250 kPa, and preferably in the range of about 50kPa to about 150 kPa, after mixing with the aqueous medium.
 34. Themethod of claim 20 wherein the mixture composition has a putty state forup to about 15 minutes, preferably up to about 8 minutes, and mostpreferably up to about 5 minutes, after mixing with the aqueous medium.35-66. (canceled)
 67. A method of repairing bone structure comprisingthe steps of: applying a composition comprising an effective amount oftetra calcium phosphate and a compound of the formula

where A is O, CH2, or S; R is H, NH2, NHCO(CH2)tCH3 where t is 0 to 2,NH(CH2)xCH3 where x is 0 to 3, NR1R2 where R1 is (CH2)yCH3 and R2 is(CH2)yCH3 where y is 0 to 2, (CH2)zCH3 where z is 0 to 3, where m is 0to 1, and where n is 0 to 3 and wherein the compound is present in anamount from about 10% to about 90% by weight based on the combinedweight of the tetra calcium phosphate and the compound directly to thebone structure to be repaired; and allowing the composition to harden bycombining in situ with aqueous based bodily fluids.
 68. The method ofclaim 67 wherein the compound is present in an amount from about 15% toabout 50% by weight based on the weight of the of the tetra calciumphosphate and the compound.
 69. The method of claim 67 wherein thecompound is present in an amount of about 20% to about 40% by weightbased on the combined weight of the of the tetra calcium phosphate andthe compound.
 70. The method of claim 67 wherein the compound isselected from the group consisting of phosphoserine, carboxy ethylphosphonate, phoshonoacetic acid, and mixtures thereof.
 71. The methodof claim 67 wherein R is H, or NH2.
 72. The method of claim 67 whereinthe compound is phosphoserine.
 73. The method of claim 67 wherein thecomposition has a mean particle size of less than 1000 microns.
 74. Themethod of claim 67 wherein the composition further includes an additive.75-86. (canceled)
 87. A method of joining bone to another materialcomprising the steps of: mixing a composition comprising an effectiveamount of tetra calcium phosphate and a compound of the formula

where A is O, CH₂, or S; R is H, NH₂, NHCO(CH₂)_(t)CH₃ where t is 0 to2, NH(CH₂)_(x)CH₃ where x is 0 to 3, NR1R2 where R1 is (CH₂)_(y)CH₃ andR2 is (CH₂)_(y)CH₃ where y is 0 to 2, (CH₂)_(z)CH₃ where z is 0 to 3,where m is 0 to 1, and where n is 0 to 3 and wherein the compound ispresent in an amount from about 10% to about 90% by weight based on thecombined weight of the tetra calcium phosphate and the compound, withsufficient aqueous medium to create a mixture; applying the mixture to asurface of the bone; placing the surface of the bone into contact with amaterial to be joined to the bone; and allowing the mixture to cure. 88.The method of claim 87 wherein the other material is a soft tissue. 89.The method of claim 87 wherein the other material is a metal.
 90. Themethod of claim 87 wherein the other material is a ceramic.
 91. Themethod of claim 87 wherein the other material is a bioglass.
 92. Themethod of claim 87 wherein the other material is bone.
 93. The method ofclaim 87 wherein the mixture is allowed to cure without the applicationof external pressure.